Secretion of Lcn2 by JAK2V617F⁺ MPN cells induces ROS and DNA damage in coexisting JAK2V617F⁻ normal cells, leading to p53 activation, cell-cycle arrest, and apoptosis. Lcn2 also induces ROS and DNA damage in JAK2V617F⁺ neoplastic cells, but an impaired p53 response in these cells may prevent growth impairment, providing them with a selective growth advantage. Lcn2-induced DNA damage could potentially contribute to acute leukemic transformation of JAK2V617F⁺ and JAK2V617F⁻ cells from MPN patients to AML.